We have isolated a novel autosomal recessive mouse mutation, which we call wrinkle-free (wrfr). wrfr-/- mice are born with taut, shiny skin, an abnormally thickened epidermis, and a defective skin barrier. The mice die during their first day of life because their skin is so tight they are unable to breathe properly. There are joint and facial defects that are secondary to the taut skin. This phenotype is very similar to that seen in a human genetic skin disease called restrictive dermopathy. We have found by positional cloning that Sic27a4, the gene which encodes fatty acid transport protein 4 (FATP4), is mutated in wrfr-/- mice. We hypothesize that fatty acid transport mediated by FATP4 plays a fundamental role in proliferation and/or differentiation of keratinocytes and establishment of the skin barrier. The goals of this proposal are to determine why mutation in FATP4 results in the wrinkle-free skin defect and how FATP4 is involved in normal skin development. The Specific Aims are to: 1) Test the hypothesis that the origin of the wrfr defect lies in the skin. We will use state-of-the-art transgenic approaches to both rescue the wrinkle-free phenotype and to specifically mutate Slc27a4 in skin. 2) Determine the normal expression pattern of FATP4 and assay the effects of its absence on expression of other proteins involved in fatty acid metabolism. We will determine by immunohistochemistry and in situ hybridization where Slc27a4 is expressed and where the FATP4 protein is localized. Expression and localization of the four other FATPs will also be investigated. 3) Determine the effects of the absence of FATP4 on fatty acid metabolism and PPAR signaling in the skin. Because some substrates of FATP4 are also ligands for PPAR family members, and PPARs are known to play a role in skin development, the wrinkle free phenotype may result from aberrant PPAR activity. 4) Graft wrfr-/- skin onto normal nude mouse skin to examine its postnatal development and capacity to form hair and other appendages. 5) Test the hypothesis that human restrictive dermopathy is caused by mutations in SLC27A4. Because fatty acid transport proteins have no defined role in skin development, the results of these experiments could open up a whole new avenue for investigation into the biology of the skin.